In case of drugs for treating chronic diseases, in order to reduce dose frequency they are prepared as sustained-release formulations, by which a therapeutically effective drug concentration can be maintained for a long period of time even by single administration only, and compliance of patients to drug therapy can be improved. Among such sustained-release formulations, polymeric microspheres have received considerable attention from many pharmaceutical companies. Examples of currently commercially available polymeric microsphere products include Risperdal Consta which is a two-week release formulation of Risperidone for treating schizophrenia, and Vivitrol which is a four-week release formulation of naltrexone for drug addiction. These formulations are typical poly(lactide-co-glycolide) (PLGA) microsphere formulations. However, they do not well release the drug at an initial stage after drug administration and the release is delayed by one to four weeks. Thus, they have to be administered inconveniently along with an oral formulation in order to obtain rapid efficacy at the initial stage.
Examples of biodegradable polymers used for preparation of microspheres include polylactide, polyglycolide, poly(lactide-co-glycolide) (PLGA) and the like. These biodegradable polymers commonly have a molecular weight of 100,000 to 200,000 daltons. The polymers have at least one terminal carboxyl acid and are thus acidic in an aqueous solution, and release organic acid such as lactic acid or glycolic acid when hydrolyzed and thus cause the neighboring environment to become acidic. For this reason, these polymers are disadvantageously unsuitable for use in drugs which are unstable to acids. In addition, since the molecular weight is considerably large, it is not easy to synthesize them as standardized polymers with uniform physical and chemical properties. For this reason, when the used batch of synthesized polymer is changed, drug release pattern from the microsphere prepared therefrom are also changed, and thus it is not easy to maintain the drug release patterns constantly. Furthermore, in order to synthesize biodegradable polymers with high molecular weight, it is necessary to use ring-opening polymerization utilizing cyclic dimers such as lactide or glycolide, the method of which requires that the synthesis be conducted in an anhydrous state. Thus, a mass-production by this method is relatively difficult. In addition, when hydrophobic drugs are applied, the polymer of microspheres starts to degrade after a predetermined time and so it is disadvantageous in that the drug efficacy is not exhibited immediately after the administration. For example, Risperdal Consta starts to release the drug about two weeks after the administration and thus it is sometimes needed to administer an oral drug for that period (M. Eerdekens et al./Schizophrenia Research 70 (2004) 91-100; S. Keith/Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 996-1008).
Accordingly, although hydrophobic drugs are applied, there is a need for development of sustained-release microparticle having a release profile in which the initial release is smoothly performed after drug administration and a level of drug in blood can be effectively maintained for a long period of time.